Acute, traumatic spinal cord injury (SCI) is a devastating clinical condition for which there is currently no effective treatment. It usually results in lifelong disability for the patient and its effect is enormous in terms of the psychological, social, and financial costs to the patient, the family and society. The neurological deficits resulting from SCI are often progressive, and result primarily from damage to the nerve fibres that carry messages up and down the spinal cord.
Despite the clinical diagnosis of "neurologically complete SCI", the spinal cord itself is rarely transected, as demonstrated by routine post-mortem histopathological investigations that have characterized the anatomical integrity of the lesion site. These observations have been corroborated by more recent noninvasive magnetic resonance imaging techniques, which have correlated changes in spinal cord tissue in the living patient with the gross clinical histopathology obtained post-mortem.
In this regard, there is increasing clinical and experimental evidence for significant preservation of descending tracts in neurologically complete SCI. In fact, use of the potassium channel blocker, 4-aminopyridine, in chronic spinal-injured cats and more recently in patients, provides strong evidence for the persistence of anatomically intact but physiologically dysfunctional descending supraspinal pathways. These drug studies in humans and in animals suggest that even though these remaining intact nerve fibres are dysfunctional, they may be induced to regain some physiologically significant function with the appropriate pharmacological intervention.
One of the histopathological hallmarks of traumatically injured spinal cord, in both clinical and experimental studies, is the presence of a central region of cavitation and necrosis (cell death), and a surviving subpial rim of tissue, composed predominantly of axons. Several theories have been proposed to account for these observations, including mechanical and vascular vulnerability of the central grey matter. However, remarkably little attention has been paid to why axons around the perimeter of the injured spinal cord survive, although morphometric analyses clearly indicate a direct relationship of axonal survival to pial depth.
Thus, it would be of considerable value to determine the factors that allow nerve fibres located around the periphery of the cord to survive while those located more centrally do not. Identification of the factors or mechanisms that allow nerve fibre survival, particularly during the early post-injury period, could possibly enable specific drug therapies to be targeted to maximize neurologic recovery in acute post-SCI cases.
There is substantial evidence in the literature that following the initial mechanical impact of traumatic CNS and spinal cord injuries, sequential and progressive tissue damage occurs at the injury site. These observations have given rise to the secondary injury hypothesis which implicates a cascade of neuropathological mechanisms in the post-traumatic destruction of spinal cord tissue. Included in the list of secondary injury mechanisms are post-traumatic ischemia and the release of excitotoxic amino acids.
Death of neurons following traumatic or ischemie disorders has been related to excess intracellular calcium which occurs, for example through excessive activation of post-synaptic glummate receptors (1,2). Considerably less is known about glial cell death, although electrophysiological and pharmacological studies indicate that glial cells probably do not have the same complement of glummate receptors as do neurons.
Glummate, a major excitatory neurotransmitter in the CNS, plays an important role in both neuronal plasticity and neurotoxicity (3). The diverse physiological functions of glutamate are reflected by the presence of distinct glutamate receptors (GluRs), which have been categorized into two major groups termed ionotropic and metabotropic (4). While ionotropic GluRs comprise integral cation-specific ion channels, the metabotropic family is coupled to intracellular signalling pathways via G-proteins.
Recent molecular (5,6) and immunocytochemical (7,8) studies have described the existence and CNS distribution of several different metabotropic glutamate receptor (mGluR) subtypes. Expression cloning (9,10), hornology screening (5,11,12)) and the subsequent functional characterization of these cloned receptors have demonstrated at least seven different subtypes (13,15). The characterization of mGluR physiology and function has been hampered by the lack of specific agonists and antagonists, although the potential suitability of a number of recently synthesized phenyl glycine derivatives has been reported (16,17).
Extensive electrophysiological and pharmacological studies have implicated mGluRs in long-term changes in neuronal signalling such as learning and memory, as well as in several neuropathological states such as epilepsy and ischemia (13). Most of the reports in the literature have clearly indicated that over-activation of GluRs leads to neuronal death or dysfunction (13,17,18).
In contrast to the vast majority of reports in the literature, there have been two studies suggesting a neuroprotective effect of mGluR activation against putative NMDA-induced neuronal damage in vitro and in vivo (19,20). Publication (20) looked at choline acetyl transferase levels after intraocular injection of NMDA with or without a non-specific mGluR agonist (trans-ACPD [(1S-cis)-1-amino-1,3-cyclopentanedicarboxylic acid]). A neuroprotective effect of trans-ACPD following focal cerebral ischemia in the mouse has also been reported (21). However, in none of the above studies, has the cell type, i.e., neuronal or glial, or the mGhR subtype been identified.
While major research efforts have been directed at an understanding of mGluR roles in neuronal cells, comparatively less information is available for glia, although there is pharmacological evidence to support the presence of mGluRs on astrocytes in culture (18).
There thus remains, at present, a serious deficiency in the in vivo treatment of traumatic injury to mammalian CNS tissue and, particularly, mammalian spinal cord injuries.